C. Omini

Prostacyclin (PGI2) in pregnant human uterus

Prostacyclin lowers the tonus and reduces the spontaneous motility of isolated pregnant human myometrium. This effect seems to be related to coclic-AMP accumulation, since PGI2 increases the formation of this cyclic nucleotide in incubated minces of pregnant and non-pregnant uterus. The ability of this tissue to generate a labile substance which inhibits platelets aggregation, has been demonstrated and discussed.

Bronchoconstriction by histamine and bradykinin in guinea pigs: Relationship to thromboxane A2 generation and the effect of aspirin

Histamine 2.5, 5, 10 or 20 microgram/kg i.v. induce a pronounced bronchospasm in guinea-pigs, accompanied by a dose-related increase of TXA2 in arterial blood, as revealed by contraction of rabbit isolated aorta and by radioimmunoassay. Aspirin 10 mg/kg prevented formation of TXA2-like material without significantly modifying the severity of the bronchospasm. Bradykinin 0.5, 1 or 2 microgram/kg i.v. acted similarly, except that pretreatment with aspirin blocked both the increased airway resistance and release of TXA2. Aspirin also blocked the increase in blood pressure and heart rate caused by histamine or bradykinin.

Antithrombotic activity of a polydeoxyribonucleotidic substance extracted from mammalian organs: A possible link with prostacyclin

Abstract The antithrombotic activity of Fraction P (FP), a polydeoxyribonucleotide extracted from mammalian organs, was studied in different models of experimental thrombosis. FP displays a remarkable protec ting activity against thrombosis induced by collagen (venous thrombosis), electrical stimulation (arterial thrombosis) and iontophoretic application of ADP (venular thrombosis). The activity of FP is long lasting and evident either by oral administration or intra venous injection. The antithrombotic activity of FP is partly due to its already reported fibrinolytic effect, but also other mechanisms which involve vascular reactivity and platelet function may come into play. The ability of FP to promote generation and release in the circulation of a deaggregating substance and to increase prostacyclin-like activity from incubated aortic tissue is discussed in order to explain the mode of action of FP in preventing thrombosis formation.

Pharmacological activity of PGI2 and its metabolite 6-OXO-PGF1α on human uterus and fallopian tubes

The actions of prostacyclin (PGI2) and its stable metabolite 6-OXO-PGF1alpha were investigated in strips of normal human uterus and in fallopian tubes. Both compounds were also compared with natural prostaglandins (PGE2, PGF2alpha and PGD2). PGI2 showed biphasic response both in uterus and fallopian tubes qualitatively and quantitatively similar to that induced by PGE2 and PGD2; prostacyclin was also able to inhibit the spasmus induced by PGF2alpha but not that induced by BaCl2 and vasopressin. 6-0XO-PGF1alpha on the other hand induced only small contractions on both tissues investigated. The authors discusse the possible implication of these findings in the physiology of the reproductive system.

Leukotriene-C4 induces generation of PGI2 and TXA2 in guinea-pig in vivo.

Summary LTC 4 administered intravenously (0.4–1.6 nmoles/kg) to anaesthetized guineapigs induces constriction of peripheral airway and fall of systemic arterial pressure preceded by a short lasting increase. These effects seem to be related with the appearance in the circulating blood of TXA 2 and PGI 2 -like activity as monitored by tonus changes of RbA and BCA. Pretreatment of the animals with aspirin (0.05 mmoles/kg i.v.) significantly reduces the effects of LTC 4 both on pulmonary mechanics and blood pressure. Lungs seem to be a source of arachidonic acid metabolites released by LTC 4 .

PGI2-generation and antithrombotic activity of orally administered defibrotide.

Abstract Defibrotide, a polydeoxyribonucleotide extracted from mammalian organs (laboratory code Fraction P), displays antithrombotic activity after oral administration on different animal species. This activity is also demonstrated in a typical local thrombonecrotic hemorrhagic lesion caused by endotoxin in rabbit (Shwartzman reaction). Defibrotide prevents and antagonizes this kind of lesion in a dose dependent and in a long lasting way. The ability of Defibrotide to increase generation of PGI2 from vascular tissue following oral administration, is demonstrated and the mechanism of this phenomenon discussed.

Effectiveness of carbocysteine lysine salt monohydrate on models of airway inflammation and hyperresponsiveness.

We investigated the possible effects of the mucoactive drug Carbocysteine lysine salt monohydrate (CLS.H2O) on experimentally-induced airway inflammation and hyperresponsiveness. CLS.H2O given by the oral route (300 mg kg(-1)) significantly reduced neutrophil infiltration into the airway lumen induced by intratracheal injection of IL-1 beta in rats. In addition, CLS.H2O inhibited dose-dependently (100-300 mg kg(-1) p.o.) the formation of pleural exudate and leukocyte recruitment induced by intrapleural injection of carrageenan in rats. Because of the close interaction between the inflammatory process and the development of airway hyperresponsiveness we also tested CLS.H2O on cigarette-smoke-induced inflammation and hyperreactivity in anaesthetized guinea-pigs. The drug, given either by oral (300 mg kg(-1)) or aerosol route (30-100 mg ml(-1)), was able to reduce the increase in airway responsiveness induced by smoke and the associated cell recruitment detected in the bronchoalveolar lavage (BAL) fluids. These results suggest that CLS.H2O can exert an anti-inflammatory action in addition to its mucoregulatory activity. The anti-inflammatory and anti-hyperreactivity effect of the drug within the airways may be of advantage in the treatment of inflammatory lung diseases where mucus secretion together with airway inflammation and hyperreactivity contribute to airway obstruction.

Defibrotide, an antithrombotic substance which prevents myocardial contracture in ischemic rabbit heart

Defibrotide, a polydeoxyribonucleotide obtained from mammalian lungs, reduced in a dose-dependent fashion the ischemic contracture due to low perfusion (0.2 ml/min) of isovolumic left heart of rabbit and abolished the irregular rhythm of the heart, thereby restoring the cardiomechanical activity upon reperfusion (20 ml/min). Defibrotide stimulated the release of PG-like material from the heart in a dose-dependent manner without modifying the basal contractility. Both PGE2 and PGI2 (10 ng/ml) have an antiischemic activity on this preparation as shown by the partial reduction of the ischemic contracture and by the improvement of heart contractility upon reperfusion. Indomethacin infusion (1 microgram/ml) completely removed both the antiischemic activity of Defibrotide (400 micrograms/ml) and its ability to increase the generation of prostaglandins in the rabbit heart. These results suggest that Defibrotide has a beneficial influence on ischemic rabbit heart through an increase in prostaglandin synthesis. However other mechanisms not necessarily related to prostaglandin generation, such as a direct effect on membrane function deactivation and mitochondrial Ca2+ overload, should be considered in explaining the antiischemic activity of Defibrotide in the rabbit heart.

Peripheral site of action of levodropropizine in experimentally-induced cough: role of sensory neuropeptides.

The mechanism of action of levodropropizine has been investigated in different models of experimentally-induced cough in guinea-pigs. In particular it has been demonstrated that the antitussive drug has a peripheral site of action by injecting the drug intracerebroventricularly (i.c.v.). In these experiments levodropropizine (40 micrograms/50 microliters i.c.v.) did not prevent electrically-induced cough. On the other hand, codeine (5 micrograms/50 microliters i.c.v.) markedly prevented coughing. A difference in the potency ratio of levodropropizine and codeine has been demonstrated in capsaicin-induced cough; after oral administration, codeine was about two to three times more potent than levodropropizine. However, after aerosol administration the two compounds were equipotent. These data might suggest a peripheral site of action for levodropropizine which is related to sensory neuropeptides. Further support for the role of sensory neuropeptides in the mechanism of action of levodropropizine comes from the results obtained in capsaicin-desensitized animals. In this experimental model levodropropizine failed to prevent the vagally elicited cough in neuropeptide-depleted animals, whereas codeine did not differentiate between control and capsaicin-treated animals. In conclusion, our results support the suggestion that levodropropizine has a peripheral site of action. In addition, the interference with the sensory neuropeptide system may explain, at least in part, its activity in experimentally-induced cough.

Isolation of a polypeptide from the venom of Bungarus multicinctus that binds to ganglia and blocks the ganglionic transmission in mammals

A 15,000 dalton polypeptide purified from Bungarus multicinctus venom (which normally copurifies with alpha-bungarotoxin) was characterized biochemically and its biological effects were studied. This polypeptide, P15, had an aminoacid composition and molecular weight different from those of both alpha- and beta-bungarotoxin. It inhibited the ganglionic transmission in the guinea-pig hypogastric nerve-vas deferens preparation and did not block, even at very high concentrations, the neuromuscular transmission in the rat phrenic nerve-diaphragm preparation. In the same preparations alpha-bungarotoxin was unable to block the response at the ganglionic synapse while it was fully active in blocking the neuromuscular transmission. However, a pretreatment of the vas deferens preparation with alpha-bungarotoxin prevented the inhibitory effect of P15. 125I-Labeled P15 showed a specific and saturable binding to rat superior cervical ganglia homogenate and to a Torpedo postsynaptic membrane fraction. The binding of P15 to ganglia was inhibited by curare. The binding was Ca2+ dependent. The density of binding sites was of 300 fmol/mg of protein in the ganglion and 500 fmol/mg of protein in Torpedo membranes. The amount of P15-binding sites in ganglia was not modified by denervation, indicating that P15 binds to postsynaptic receptors. The binding of 125I-labeled P15, both in ganglia and Torpedo membranes, was inhibited by alpha-bungarotoxin. P15 had a Ca2+-dependent phospholipase A2 activity. Lowering Ca2+ concentration in incubation media affected the phospholipase A2 activity more than binding properties and inhibition of phospholipase activity with p-bromophenacyl bromide did not affect the activity of P15 on vas deferens preparation, suggesting that the phospholipase activity is not necessary for the activity of P15 on nicotinic receptors. Our results suggest that P15 toxin may be a specific and valuable probe for studying the ganglionic nicotinic receptor.